SUMMARY/ABSTRACT Data have revealed increases in cardiovascular (CVD) and neurodegenerative diseases in First Responders (FR) who were present at the Ground Zero over the 9/11-13/01 period. While it has yet not been shown if WTC (World Trade Center) dusts were causative for these pathologies in FR, our study of SHR rats exposed to WTC dusts [in paradigms mimicking mouthbreathing FR] noted significantly changes in CV function and cardiac gap junction protein expression, and ultrastructural remodeling like that seen in heart failure. These rats also had persistent (up to 1 yr post-exposure) reductions in airway ciliated cells and dust clearance from the lung. It is thus likely exposures to WTC dusts resulted in exaggerated responses in situ compared to that by other urban air pollutants, including particulate matter (PM). We know long-term exposure to ambient PM caused a heart failure phenotype in mice (decreased cardiac function and impaired cell function) and neurologic as well as Alzheimer disease (AD)-like changes (increased levels of BACE protein, APP processing, and A? [amyloid-?]) in their brains. As both CVD and AD are age-related, share risk-factors, have overlapping bio-chemistries, and are characterized by aggregates of amyloid precursor protein (found in AD brains and CVD hearts), based on the ?heart-to-head? pathogenesis paradigm, we hypothesize here that inhalation of Ground Zero dust particles likely led - in a manner exaggerating that caused by PM - to alterations in cardiac and cognitive function, so as to impart severe chronic impacts on FR health. As models, SHR rats will be exposed to WTC dust (using paradigms as in current WTC project: 2 consecutive days, 2 hr/d, intratracheal inhalation, using dusts collected on-site 9/12-13/01). Both longitudinally and at fixed timepoints over a 1-yr post-exposure period, data will be obtained in support of two inter-related Aims. Aim 1 will define effects of WTC dust exposures on CV function and A? aggregate accumulation in the heart. Aim 2 will assess effects of the exposures on development of neurodegenerative disease. We are aware there is as-yet no documented link between AD and FR exposures at Ground Zero. However, as with the long-expected increased risk for lung cancer, one cannot outright preclude a possibility of this specific pathology developing simply due to absence of epidemiologic data to- date. Accordingly, in a Supplemental Aim, exposed rats will undergo additional cognitive studies and brain levels of Neuropeptide-Y and N-acetylaspartate will be examined to see if there were changes induced over time reflective of PTSD, an well-documented outcome among exposed FR. The studies will allow us, for the first time, to determine the time-course of any WTC dust-induced onset/progression of CV dysfunction and neurodegenerative disorders in exposed hosts. The studies address NIOSH goals (CVD Cross-Sector Program, Public Safety Program [Priority 1: Reduce chronic illnesses among firefighters] and FFFFIPP [Goal 1: Reduce CV deaths among firefighters]), keep with major r2p initiatives to reduce illness among firefighters/FR via NIOSH-generated knowledge, interventions, technologies, and fulfill the Zadroga Act research mandate.